Lung cancer is one of the major causes of cancer-related deaths in the world. There are two primary types of lung cancers: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) (Carney, (1992a) Curr. Opin. Oncol. 4: 292-8). Small cell lung cancer accounts for approximately 25% of lung cancer and spreads aggressively (Smyth et al. (1986) Q J Med. 61: 969-76; Carney, (1992b) Lancet 339: 843-6). Non-small cell lung cancer represents the majority (about 75%) of lung cancer and is further divided into three main subtypes: squamous cell carcinoma, adenocarcinoma, and large cell carcinoma (Ihde and Minna, (1991) Cancer 15: 105-54). In recent years, much progress has been made toward understanding the molecular and cellular biology of lung cancers. Many important contributions have been made by the identification of several key genetic factors associated with lung cancers. However, the treatments of lung cancers still mainly depend on surgery, chemotherapy, and radiotherapy. This is because the molecular mechanisms underlying the pathogenesis of lung cancers remain largely unclear.
A recent hypothesis suggested that lung cancer is caused by genetic mutations of at least 10 to 20 genes (Sethi, (1997) BMJ. 314: 652-655). Therefore, future strategies for the prevention and treatment of lung cancers will be focused on the elucidation of these genetic substrates, in particular, the genes associated with the cell cycle regulation in lung cancers since it is believed that dysregulation of cell cycle may lead to the initiation and progression of cancers. Cyclins, regulators of cell cycle in eukaryotic cells (Hunter and Pines, (1991) Cell 66:1071-4), have been shown to be associated with cancers (Hunter and Pines, (1991) Cell 66:1071-4; Lammie et al. (1991) Oncogene 6:439-44; Jiang et al. (1992) Cancer Res 52:2980-3; Keyomarsi and Pardee, (1993) Proc Natl Acad Sci U S A 90:1112-6; Weinstat-Saslow et al. (1995) Nat Med 1:1257-60). Cyclin G, a member of the cyclin family, has been shown to be associated with the carcinogenic process (Skotzko et al. (1995) Cancer Res 55:5493-8; Reimer et al. (1999) J Biol Chem 274:11022-9) mediated via p53 (a tumor suppressor gene) cell growth regulatory pathways (Okamoto and Beach, (1994) EMBO J 13:4816-22; Home et al. (1996) J Biol Chem 271:6050-61; Bates et al. (1996) Oncogene 13:1103-9; Smith et al. (1997) Exp Cell Res 230:61-8). The involvement of p53 gene in NSCLC (Kohno et al. (1999) Cancer 85: 341-7) suggests that the genes associated with cyclin G may be involved in the carcinogenesis of lung cancers. Therefore, the cyclin G-associated protein kinase (GAK), a partner of cyclin G (Kanaoka et al. (1997) FEBS Lett 402:73-80), is expected to be an important molecule for lung cancers.
The human GAK gene (Kimura et al. (1997) Genomics 44:179-87) contains an open reading frame (ORP) of 3933 bp encoding 1311 amino acids. Sequence analysis demonstrated that GAK contains a Ser/Thr kinase domain, a tensin/auxilin homologous domain, and a Tyr phosphorylation target site. Using FISH technique, GAK was assigned to the chromosome 4p16 (Kimura et al. (1997) Genomics 44:179-87), a chromosomal region frequently altered in lung cancers (Michelland et al. (1999) Cancer Genet Cytogenet 114:22-30). Taken together with the discovery of gene variants of NOC2 (localized on chromosome 17p) as potential diagnostic markers for lung cancers (U.S. patent Ser. No. 09/964,275), we believe that the discovery of GAK-related gene variants may also be important targets for diagnostic markers of lung cancers.